ClinVar Miner

Submissions for variant NM_000481.3(AMT):c.878-1G>A (rs181134220)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012761 SCV000793040 pathogenic Non-ketotic hyperglycinemia 2017-07-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012761 SCV000916445 pathogenic Non-ketotic hyperglycinemia 2018-03-08 criteria provided, single submitter clinical testing Variant summary: AMT c.878-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.9e-05 in 260824 control chromosomes. c.878-1G>A has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000012761 SCV000935304 pathogenic Non-ketotic hyperglycinemia 2019-10-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the AMT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs181134220, ExAC 0.002%). This variant has been observed in homozygous form and in combination with another AMT variant in several individuals affected with glycine encephalopathy (PMID: 11139253, 12948742, Invitae). ClinVar contains an entry for this variant (Variation ID: 11981). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012761 SCV000032996 pathogenic Non-ketotic hyperglycinemia 2001-01-01 no assertion criteria provided literature only
GeneReviews RCV000012761 SCV000086788 pathologic Non-ketotic hyperglycinemia 2013-07-11 no assertion criteria provided curation Converted during submission to Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.